Inhibitors of akt activity

Abstract

Invented are novel 1H-imidazo[4,5-c]pyridin-2-yl compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.

1 . A compound selected from:
 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;   4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;   4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol; and   4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2-morpholinyl]methyl}oxy)-1H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;   
       or a pharmaceutically acceptable salts thereof. 
     
     
         2 . A compound of  claim 1  that is:
 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;   
       or a pharmaceutically acceptable salts thereof. 
     
     
         3 . A compound of  claim 1  that is:
 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;   
       or a pharmaceutically acceptable salts thereof. 
     
     
         4 . A compound of  claim 1  that is:
 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;   
       or a pharmaceutically acceptable salts thereof. 
     
     
         5 . A compound of  claim 1  that is:
 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2-morpholinyl]methyl}oxy)-1H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;   
       or a pharmaceutically acceptable salts thereof. 
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         7 . A pharmaceutical composition comprising a compound according to  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         8 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier and an effective amount of a compound of  claim 1 , which process comprises bringing the compound of  claim 1  into association with a pharmaceutically acceptable carrier. 
     
     
         9 . A method of treating or lessening the severity of a disease or condition selected from cancer and arthritis in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of  claim 1 . 
     
     
         10 . The method of  claim 9  wherein the mammal is a human. 
     
     
         11 . A method of treating or lessening the severity of a disease or condition selected from cancer and arthritis in a human in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of  claim 2 . 
     
     
         12 . (canceled) 
     
     
         13 . The method according to  claim 10  wherein said cancer is selected from brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid. 
     
     
         14 . The method according to  claim 11  wherein said cancer is selected from brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid. 
     
     
         15 . (canceled) 
     
     
         16 . The method of inhibiting Akt activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16  wherein the mammal is a human. 
     
     
         18 . A method of treating cancer in a human in need thereof, which comprises: co-administering to such human a therapeutically effective amount of
 a) a compound of  claim 1 ; and   b) at least one anti-neoplastic agent.   
     
     
         19 . The method  claim 18 , wherein the at least one anti-neoplastic agent is selected from the group consisting essentially of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. 
     
     
         20 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is an anti-microtubule agent selected from diterpenoids and vinca alkaloids. 
     
     
         21 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is a diterpenoid. 
     
     
         22 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is a vinca alkaloid. 
     
     
         23 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is a platinum coordination complex. 
     
     
         24 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is paclitaxel, carboplatin, or vinorelbine. 
     
     
         25 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is paclitaxel. 
     
     
         26 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is carboplatin. 
     
     
         27 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is vinorelbine. 
     
     
         28 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is a signal transduction pathway inhibitor. 
     
     
         29 . The method of  claim 28 , wherein the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase selected from the group consisting of VEGFR2, TIE2, PDGFR, BTK, IGFR-1, TrkA, TrkB, TrkC, and c-fms. 
     
     
         30 . The method of  claim 28 , wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of rafk, akt, and PKC-zeta. 
     
     
         31 . The method of  claim 28 , wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the src family of kinases. 
     
     
         32 . The method of  claim 31 , wherein the signal transduction pathway inhibitor is an inhibitor of c-src. 
     
     
         33 . The method of  claim 28 , wherein the signal transduction pathway inhibitor is an inhibitor of Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase. 
     
     
         34 . The method of  claim 28 , wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of PI3K. 
     
     
         35 . The method of  claim 18 , wherein the at least one anti-neoplastic agent is a cell cycle signaling inhibitor. 
     
     
         36 . The method of  claim 35 , wherein the cell cycle signaling inhibitor is selected from inhibitors of the group CDK2, CDK4, and CDK6. 
     
     
         37 - 38 . (canceled) 
     
     
         39 . A method of treating or lessening the severity of a disease or condition selected from cancer and arthritis in a human in need thereof, which comprises administering to such mammal a therapeutically effective amount of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol for a pharmaceutically acceptable salt. 
     
     
         40 . A method of treating or lessening the severity of a disease or condition selected from cancer and arthritis in a human in need thereof, which comprises administering to such mammal a therapeutically effective amount of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol or a pharmaceutically acceptable salt. 
     
     
         41 . A method of treating or lessening the severity of a disease or condition selected from cancer and arthritis in a human in need thereof, which comprises administering to such mammal a therapeutically effective amount of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol or a pharmaceutically acceptable salt. 
     
     
         42 . A method of treating or lessening the severity of a disease or condition selected from cancer and arthritis in a human in need thereof, which comprises administering to such mammal a therapeutically effective amount of 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2-morpholinyl]methyl}oxy)-1H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol or a pharmaceutically acceptable salt.